Use of cathepsin k inhibitors for the treatment of glaucoma

ABSTRACT

Compositions containing inhibitors of cathepsin K (CTSK) expression and/or activity are provided. Methods for the treatment of glaucoma using the compositions of the invention are further provided.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the field of glaucoma treatment. Morespecifically, the present invention involves the use of antagonists ofcathepsin K (CTSK) activity and/or signaling leading to expression, inorder to treat glaucoma or ocular hypertension.

2. Description of the Related Art

The disease state referred to as glaucoma is characterized by apermanent loss of visual function due to irreversible damage to theoptic nerve. Morphologically or functionally distinct types of glaucomaare typically characterized by elevated intraocular pressure (IOP),which is considered to be causally related to the pathological course ofthe disease. Disruption of normal aqueous outflow leading to elevatedIOP is integral to glaucoma pathophysiology. Ocular hypertension is acondition wherein IOP is elevated but no apparent loss of visualfunction has occurred; such patients are considered to be at high riskfor the eventual development of the visual loss associated withglaucoma. Some patients with glaucomatous field loss have relatively lowIOPs. These so called normotension or low tension glaucoma patients canalso benefit from agents that lower and control IOP. Drug therapies thathave proven to be effective for the reduction of IOP include both agentsthat decrease aqueous humor production and agents that increase theoutflow facility. Such therapies are, in general, administered by one oftwo possible routes, topically (direct application to the eye) ororally.

Elevated IOP, found in most glaucoma patients, is a result ofmorphological and biochemical changes in the trabecular meshwork (TM),an aqueous humor filtering tissue located at the iris-cornea angle ofthe eye. As glaucoma progresses, there is a loss of TM cells and abuildup of extracellular products which inhibit the normal aqueous humoroutflow resulting in IOP elevation. In addition to elevated IOP,ischemia, excitotoxicity and other factors may lead to mechanicaldistortion of the optic nerve head (ONH) ultimately resulting in ONHcupping and loss of retinal ganglion cells (RGC) and axons. The exactmechanism of this pathological process is currently unknown.

The discrimination of the various forms of glaucoma has progressed sincethe discovery of the primary open angle glaucoma (POAG) gene MYOC in theGLC1A locus. Over 15 different glaucoma genes have been mapped and sevenglaucoma genes identified. Two POAG genes (MYOC and OPTN) have beenidentified from the six mapped genes (GLC1A-GLC1F). One congenitalglaucoma gene (CYP1B1) has been identified from the three mapped genes(GLC3A-GLC3B). Four developmental or syndromic forms of glaucoma (FOXC1,PITX2, LMX1B, PAX6) have been identified and two genes have been mappedfor pigmentary dispersion/pigmentary glaucoma.

It is likely that multiple disease mechanisms are at work in the variousglaucomas and will require specific therapies tailored to each disorder.For example, a drug that effects the expression of enzymes that degradethe extracellular matrix (ECM) of the ONH may not necessarily preventRGC death caused by excitotoxicity or neurotrophic factor deficit. Onthe other hand, many different insults, for example apoptosis of RGCs,may converge at a common point or points that are amenable to drugtherapy. Current anti-glaucoma therapy is based on lowering IOP by theuse of suppressants of aqueous humor formation, agents that enhanceuveoscleral outflow, trabeculoplasty, or trabeculectomy. These currenttherapies do not directly address the pathological damage to thetrabecular meshwork, which continues unabated. It would be advantageousto have a therapeutic product including an agent that directlyinterferes with the pathogenic process.

Cathepsins are members of the papain family of cysteine proteases.Cathepsin K (CTSK, previously known as cathepsin O or cathepsin O2) isinvolved in osteoclast bone resorption and bone remodeling. CTSKdisplays endoprotease activity against fibrinogen, has highelastinolytic and collagenolytic activities and may play an importantrole in extracellular matrix degradation. CTSK is a lysosomal enzymewith selective expression in osteoclasts and embryo/fetal respiratoryand gastrointestinal mucosa. CTSK is highly expressed in human ciliarybody epithelial cells (pigmented and non-pigmented), iris, and retinalpigment epithelium but not cornea, lens, or retina and has not beenprofiled in the trabecular meshwork (Ortega et al. 1997).

The identification of CTSK involvement in glaucoma pathogenesis and theuse of expression or activity inhibitors as presented herein has notbeen previously described.

SUMMARY OF THE INVENTION

The present invention overcomes drawbacks of the prior art by providingcompounds targeted to a specific gene product to protect or rescuepatients from the damage caused by glaucoma. Specifically, the presentinvention is drawn to compositions for methods of treating glaucoma(with or without elevated IOP) and ocular hypertension through theadministration of one or more CTSK inhibitors.

The method comprises administering to the subject a therapeuticallyeffective amount of a composition including at least one non-nucleotideor non-protein agent that inhibits expression and/or signaling leadingto expression of CTSK, and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

FIG. 1 is a photographic depiction that illustrates results ofdifferential cDNA subtraction hybridization (FIG. 1A) and VirtualNorthern Blot analysis (FIG. 1B) of CTSK in glaucomatous vs. normal TMcell lines.

FIG. 2 is a graph depicting quantitative polymerase chain reaction (PCR)analysis of CTSK expression in pooled normal or glaucomatous TM celllines.

FIG. 3 is a graph depicting Affymetrix GeneChip U133A analysis of pooledNTM or GTM cell lines.

DETAILED DESCRIPTION PREFERRED EMBODIMENTS

According to the present invention, the protease CTSK has beenidentified as being up-regulated in glaucomatous TM cells and tissues.Expression of CTSK under these conditions indicates a causal or effectorrole for CTSK in glaucoma pathogenesis. It has been found that elevatedlevels of CTSK may function pathophysiologically by destroyingextracellular matrix required for normal filtration and cellularfunction in the TM. Disruption of normal aqueous outflow leading toelevated IOP is integral to glaucoma pathophysiology. The presentinvention is directed to the use of antagonists of CTSK in the treatmentof glaucoma. The advantage of the present invention is that a specificgene product has been identified to which specific compounds may betargeted to protect or rescue patients from the damage caused byglaucoma. The compositions and methods of the present invention areintended to directly interfere with the pathogenic process.

This invention is directed to the treatment of glaucoma by theinhibition of CTSK. It is contemplated that any CTSK inhibiting compoundwill be useful in the methods of the present invention. The inventorscontemplate that any of the compounds disclosed in U.S. Pat. Nos.5,830,850; 6,057,362; 5,998,470; and 6,034,077 (all incorporated hereinby reference); or described in the literature (Altmann et al. 2002;Billington et al. 2000; Bossard et al. 1999; Bromme et al. 1996;Falgueyret et al. 2001; Fenwick et al. 2001a; Fenwick et al. 2001b;Kamolmatyakul et al. 2001; Katunuma et al. 2000; Katunuma et al. 1999;LaLonde et al. 1998; Lark et al. 2002; Leung-Toung et al. 2002; Marquiset al. 2001a; Marquis et al. 1999; Marquis et al. 2001b; Marquis et al.1998; Matsumoto et al. 1999; McGrath et al. 1997; Patil et al. 2002a &b; Percival et al. 1999; Schick et al. 1998; Smith et al. 2001; Stroupet al. 2001; Thompson et al. 1997; Thompson et al. 1999; Thompson et al.1998; Turk et al. 1997; Votta et al. 1997; Yamashita and Dodds 2000;Yamashita et al. 1999; Zhao et al. 1997; all incorporated herein byreference) would be suitable for use in the compositions and methods ofthe present invention.

More specifically, preferred CTSK antagonists for use in the presentinvention include, but are not limited to, monensin, brefeldin A,tunicamycin and 1,3-bis(acylamino)-2-propanone derivatives, cathepsin Kantisense, triple helix and/or ribozyme molecules, inhibitors ofcathepsin K enzymatic activity, azepanone-based inhibitors, cyclicketones, fluoromethyl ketones, vinyl sulfones, peptide aldehydes,nitriles, α-ketocarbonyl compounds, including α-diketones,α-keto-esters, α-ketoamides, and α-ketoacids, halomethyl ketones,diazomethyl ketones, (acyloxy)-methyl ketones, ketomethylsulfoniumsalts, epoxy succinyl compounds, cycloaltilisin 6, cycloaltilisin 7,AC-3-1, AC-3-3, AC-5-1, haploscleridamine,5-(2-morpholin-4-yl-thoxy)-benzofuran-2-carboxylic acid((S)-3-methyl-1-[3-oxo-1-[2-(3-pyridin-2-yl-phenyl)-ethenoyl]-azepan-4-ylcarbanoyl)-butyl)-amide(SB-331750), SB-357114 (Stroup et al. 2001), peptidomimetic aminomethylketones, α,α′-diacylamino ketones, alkoxymethyl ketones, cyanamides,pyridoxal propionate derivatives (including Clik-164 and Clik-166),SB-290190 (Leung-Toung et al. 2002), α-alkoxyketone derivatives,cyanamide derivatives, and arylaminoethyl amides such asN_(α)-acyl-α-amino acid-(arylaminoethyl)amides (Altmann et al. 2002).Additional preferred compounds include:

-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboxamidothiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-cyanothiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyoxycarbonyl)amino-N-[1′-[2-(N-benzylcarboxamido)thiazol-4-yl]-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-[2-[N′-3-methylpropyl)carboxamido]thiazol-4-yl)]-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-[2-[N′-2-phenylethyl)    carboxamido]thiazol-4-yl)]-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxythiadiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carbo-2,2,2-trifluoroethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxyoxadiazol-2-yl)-3′-methylbutyl]4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboxamidooxadiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-3-phenylpropanamide;-   (2S,1′S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(5-mercapto-1,2,4-oxadiazol-3-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-mercaptothiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S)-2-(benzyloxycarbonyl)amino-N-(4-carboethoxythiazol-2-yl)methyl-4-methyl    pentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-benzyloxycarbonylthiazol-4-yl]-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-4-methyl-N-[3′-methyl-1′-(2-phenoxycarbonylthiazol-4-yl)butyl]pentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-4-methyl-N-[3′-methyl-1′-[2-(2-methylpropyloxy    carbonyl)thiazol-4-yl]butyl]pentanamide;-   (2R,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(carboethoxythiazol-2-yl)ethyl]4-methylpentanamide;-   (2R,1′R)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carbethoxythiazol-2-yl)ethyl]-4-methylpentanamide;-   (2S,1′S)-N-[1′-(2-aminothiazol-4-yl)-3′-methylbutyl]-2-(benzyloxycarbonyl)amino-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;-   (2S,1′S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;-   (1S)-N-[4-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N′-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;-   N-benzyloxycarbonyl-L-leucinyl-N′-benzyloxycarbonyl-L-leucinyl-L-leucinylhydrazide;-   (1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;-   2,2′-(N,N′-bis-benzyloxycarbonyl-L-leucinyl)carbohydrazide;-   2,2′-(N,N′-bis-cyclohexylacetyl)carbohydrazide;-   2,2′-(N,N′-bis-4-methylpentanoyl)carbohydrazide;-   2,2′-(N,N′-bis-cyclopentylacetyl)carbohydrazide;-   2,2′-(N,N′-bis-benzyloxycarbonylglycinyl)carbohydrazide;-   2,2′-(N,N′-bis-acetyl-L-leucinyl)carbohydrazide;-   2,2′-(N,N′-bis-benzyloxycarbonyl-L-alanyl)carbohydrazide;-   2-(N-benzyloxycarbonyl-L-leucinyl)-2′-[N′-(4-methylpentanoyl)]carbohydrazide;-   2,2′-(N,N′-bis-benzyloxycarbonyl-L-leucinyl)carbohydrazide;-   bis-(Cbz-leucinyl)-1,3-diamino-propan-2-one;-   bis-1,3-(4-phenoxy-benzoyl)-diamino-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl-t-butyl    ester)-amino-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl)-amino-propan-2-one;-   bis-1,3-(Cbz-leucinyl)-diamino-(S)-butanone-2-one;-   1-(Cbz-leucinyl)-amino-3-(Cbz-phenylalanyl)-amino-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(Cbz-norleucinyl)-amino-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(Cbz-norvalinyl)-amino-propan-2-one;-   bis-1,3-(Cbz-leucinyl)-diamino-5-methyl-(S)-hexan-2-one;-   1-(acetyl-leucinyl)-amino-3-(4-phenoxy-benzoyl)-amino-propan-2-one;-   1-(Cbz-homo-leucinyl)-amino-(Cbz-leucinyl)-3-amino-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one;-   bis-1,3-(4-(3-chloro-2-cyano-phenoxy)-phenyl    sulfonamido)-propan-2-one;-   bis-1,3-(4-phenoxy-phenyl sulfonamido)-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenyl    sulfonamido)-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(tosyl-amino)-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one;-   1-(Cbz-homo-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one;-   1-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one;-   1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one;-   (S)-Phenylmethyl    [1-[[[3-[benzyloxycarbonyl-leucinyl-amino]-2-oxopropyl]-1-(benzyl)amino]carbonyl]-3-methylbutyl]carbamate;-   (S)-Phenylmethyl    [1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(benzyl)amino]carbonyl]-3-methylbutyl]carbamate;-   (S)-Phenylmethyl    [1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate;-   1-[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4-pyridinylmethyl)]benzamide;-   (S)-Phenylmethyl    [1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-1-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate;-   (S)-Phenylmethyl    [1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-1-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenoxyphenylsulfonyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-alanyl)]-2′-[N-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenylbenzoyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′4-methoxybenzoyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenoxybenzoyl)]carbohydrazide;-   2-(N-acetyl)-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;-   2-[N-(N-acetyl-L-leucinyl)]-2′-[N′-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide;-   2-[N-(N-acetyl-L-alanyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-N,N-dimethylaminomethyl)    benzoyl)]]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-hydroxy-[3-(4-morpholinomethyl)]]benzoyl]carbohydrazide;-   2-[N-N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-[N,N-dimethylaminomethyl)    benzyloxy]carbonyl-L-leucinyl]carbohydrazide;-   2-(N-benzoyl)-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[3-(4-morpholinomethyl)benzoyl]]carbohydrazide;-   2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-[3-N-N-dimethylamino)-1-propyloxy]benzoyl]]carbohydrazide;-   2-[N-(2-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[3-(4-pyridylmethoxy)benzoyl]]carbohydrazide;-   2-[N-(4-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(3-benzyloxy-5-methoxy)benzoyl]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(3-benzyloxy-4,5-dimethoxy)    benzoyl]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(3-benzyloxy-5-ethoxy)    benzoyl]carbohydrazide;-   2-[N-(N-benzyloxycarbonylglycinyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;-   2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-prolinyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenylphenylacetyl)]carbohydrazide;-   (2′S)-2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-2-aminobutyryl)]carbohydrazide;-   2,2′-[N,N′-[bis-4-phenylphenylacetyl)]]carbohydrazide;-   (2′RS)-2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[2-(4-phenylphenoxy)propionyl]carbohydrazide;-   2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(4-methylpentanoyl)]carbohydrazide;-   (2RS,2′RS)-2,2′-[N,N′-[bis-[2-(4-phenylphenyl)-4-methylpentanoyl)]]]carbohydrazide;-   (2′RS)-2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;-   (2′RS)-2-[N-(3-benzyloxybenzoyl)]-2′-[N-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;-   2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)]carbohydrazide;-   2-[N-(3-benzyloxybenzoyl)]-2′-[N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;-   2-[N-[3-(4-pyridylmethoxy)benzoyl]]-2′-[N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;-   (2RS)-2-[N-[2-(4-phenylphenyl)-4-methylpentanoyl)]]-2′-[N′-[N-(2-pyridinylmethoxy    carbonyl)-L-leucinyl]]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N-[2-4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[N-(4-phenylphenyl)-N-(2-methylpropyl)    carbamoyl]]carbohydrazide;-   2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-methyl-L-leucinyl)]carbohydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(N-methyl-L-leucinyl)]carbohydrazide;-   (1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-(4-phenoxyphenylsulfonyl)hydrazide;-   (1S)-N-[4-[1-(N-benzyloxycarbonyl-L-leucinylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N′-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;-   (1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-(4-phenylphenylacetyl)hydrazide;-   (1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-[3-(4-pryidinylmethoxy)benzoyl]hydrazide;-   N-[2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;-   N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N′-[2-[4-(1,2,3-thiadiazol-4-yl)phenyl]thiazol-4-ylcarbonyl]hydrazide;-   N-[2-[3-(4-chlorophenylsulfonylmethyl)thien-2-yl]thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;-   (1S,2′RS)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-[2′-(4-phenylphenylacetyl)-4-methylpentanoyl-]hydrazide;-   N-[2-(3-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;-   (1RS)-N-[2-[1-(4-phenylphenyl)-3-methylbutyl]thiazolylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;-   N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;-   N-[2-[N-methyl-N-(4-phenylphenyl)amino]thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinyl    methoxycarbonyl)-L-leucinyl]hydrazide;-   N-(N-benzyloxycarbonyl-L-leucinyl)-N′-[2-(4-phenylbenzyl)thiazol-4-ylcarbonyl]hydrazide;-   N-[2-(4-phenylphenylbenzyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;-   N-(N-benzyloxycarbonyl-L-leucinyl)-N′-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]hydrazide;-   N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N′-N-(4-pyridinyl    methoxycarbonyl)-L-leucinyl]hydrazide;-   N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;-   N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;-   N-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)-N′-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]hydrazide;-   N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N′-[N-(2-pyridinyl    methoxycarbonyl)-L-leucinyl]hydrazide;-   N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N′-[N-(3-pyridinyl    methoxycarbonyl)-L-leucinyl]hydrazide;-   N-[2-(2-methoxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;-   2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-(N,N-dimethylaminomethyl)    benzyloxy]carbonyl-L-leucinyl]carbonhydrazide;-   (3S,4S)-3-(2S-2-benzyloxycarbonylamino-2-cyclohexyl-methyl-acetamido)-4-acetoxy-azetidin-2-one;-   (3S,4S)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-acetoxy-azetidin-2-one;-   (3S,4S)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-{4-(2S-2-amino-2-carboxy-ethyl)-phenoxy}-azetidin-2-one;-   (3S,4R)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-{4-(2S-2-amino-2-carboxy-ethyl)-phenoxy}-azetidin-2-one;-   (3S,4SR)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}4-phenylthio-azetidin-2-one;-   (3S,4SR)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-phenylsulfonyl-azetidin-2-one;-   (3S,4S)-3-{2S-2-(benzylaminocarbonyl)amino-2-cyclo-hexylmethyl-acetamido}-4-acetoxy-azetidin-2-one;-   (3S,4S)-3-{2S-2-(phenylethenylsulfonyl)amino-2-cyclohexylmethyl-acetamido}-4-acetoxy-azetidin-2-one;-   (3S,4S)-3-(2S-2-benzyloxycarbonylamino-2-cyclohexylmethyl-acetamido)-4-(3-methyl-phenoxy)-azetidin-2-one;-   (3S,4R)-3-(2S-2-benzyloxycarbonyl    amino-2-cyclohexymethyl-acetamido)-4-(3-methyl-phenoxy)-azetidin-2-one;-   (3S,4S)-3-{2S-2-[3-(pyridin-4-yl)    propenoyl]amino-2-cyclohexylmethyl-acetamido}-4-phenoxy-azetidin-2-one;    and-   (3S,4S)-3-{2S-2-[3-(pyridin-3-yl)propenoyl]amino-2-cyclohexylmethyl-acetamido}4-phenoxy-azetidin-2-one.

Additional inhibitors of CTSK may be identified by one skilled in theart by using enzyme assays with a known small peptide fluorogenicsubstrate for CTSK. A specific CTSK substrate used may be the cleavablefluorogenic peptide Z-Phe-Arg-AMC(phenylalanine-arginine-aminomethylcoumarin; Bachem Biosciences, Inc.,King of Prussia, Pa.) (Votta, Levy et al. 1997). Hydrolysis of thispeptide by CTSK may be followed by changes in fluorescence versus timein the presence or absence of selected CTSK inhibitors.

The inventors are unaware of any previous teaching of the use of thesecompounds for lowering and controlling normal or elevated intraocularpressure (IOP) and treating glaucoma

While bound by no therories, the fundamental principle behind using CTSKantagonists in the treatment of glaucoma is that elevated levels of thisenzyme may function pathophysiologically by destroying extracellularmatrix required for normal filtration and cellular function in thetrabecular meshwork (TM). CTSK antagonists may be administeredsystemically either orally or intravenously or specifically to the eyevia topical or intravitreal injection. The compounds that are useful asCTSK antagonists in the methods of this invention (Compounds) includeany and all compounds that inhibit or antagonize CTSK. Such Compoundscan be incorporated into various types of ophthalmic formulations fordelivery to the eye (e.g., topically, intracamerally, or via animplant). The Compounds are preferably incorporated into topicalophthalmic formulations for delivery to the eye. The Compounds may becombined with ophthalmologically acceptable preservatives, surfactants,viscosity enhancers, penetration enhancers, buffers, sodium chloride,and water to form an aqueous, sterile ophthalmic suspension or solution.Ophthalmic solution formulations may be prepared by dissolving aCompound in a physiologically acceptable isotonic aqueous buffer.Further, the ophthalmic solution may include an ophthalmologicallyacceptable surfactant to assist in dissolving the Compound. Furthermore,the ophthalmic solution may contain an agent to increase viscosity, suchas, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, orthe like, to improve the retention of the formulation in theconjunctival sac. Gelling agents can also be used, including, but notlimited to, gellan and xanthan gum. In order to prepare sterileophthamic ointment formulations, the active ingredient is combined witha preservative in an appropriate vehicle, such as, mineral oil, liquidlanolin, or white petrolatum. Sterile ophthalmic gel formulations may beprepared by suspending the Compound in a hydrophilic base prepared fromthe combination of, for example, carbopol-974, (BF Goodrich, Charlotte,N.C.) or the like, according to the published formulations for analogousophthalmic preparations; preservatives and tonicity agents can beincorporated.

The Compounds are preferably formulated as topical ophthalmicsuspensions or solutions, with a pH of about 4 to 8. The establishmentof a specific dosage regimen for each individual is left to thediscretion of the clinicians. The Compounds will normally be containedin these formulations in an amount 0.01% to 5% by weight, but preferablyin an amount of 0.05% to 2% and most preferably in an amount 0.1 to 1.0%by weight. The dosage form may be a solution, suspension, ormicroemulsion. Thus, for topical presentation 1 to 2 drops of theseformulations would be delivered to the surface of the eye 1 to 4 timesper day according to the discretion of a skilled clinician.

The Compounds can also be used in combination with other agents fortreating glaucoma, such as, but not limited to, β-blockers (preferablytimolol, betaxolol, or levobetaxolol), prostaglandins and analoguesthereof (preferably travoprost, latanoprost or bimatoprost), carbonicanhydrase inhibitors (preferably acetazolamide or dorzolamide), α₂agonists (preferably aproclonidine or brimonidine), miotics, andneuroprotectants.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventors to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1 cDNA Subtraction Screen & Virtual Northern Blot Analysis

CTSK was originally identified in a custom PCR-Select cDNA subtractionscreen (Clontech, Palo Alto, Calif.) as being more abundant inglaucomatous than normal TM cells. Human TM cells were derived fromdonor eyes (Central Florida Lions Eye and Tissue Bank, Tampa, Fla.) andcultured as previously described (Steely, Browder et al. 1992; Wilson,McCartney et al. 1993; Clark, Wilson et al. 1994; Dickerson, Steely etal. 1998; Wang, McNatt et al. 2001).

The cDNA subtraction procedure was essentially performed as follows.Total RNA (700 μg) was isolated from pooled normal (NTM10C, NTM69C,NTM96, NTM57C, NTM53A, NTM95, and NTM93) or glaucomatous TM cell lines(GTM999, GTM59B, GTM19, GTM62, GTM29, and GTM86) as described by Shepardet al. (2001). Poly A+ RNA was subsequently isolated from the total RNAby two rounds of selection with oligo-dT latex beads using a NucleotrapmRNA Midi kit (Clontech, Palo Alto, Calif.). PCR-Select cDNA subtractionwas then performed according to the manufacturers instructions(Clontech, Palo Alto, Calif.).

Screening of the cDNA subtraction libraries was performed by PCR-SelectDifferential Screening according to the manufacturers instructions(Clontech, Palo Alto, Calif.). Five x 96-well plates of subtracted cDNAclones were subjected to differenteial screening analysis (FIG. 1A).Differentially expressed cDNA clones were ordered by relative abundanceand CTSK was identified as the most abundant clone. CTSK was alsoconfirmed by Virtual Northern blot analysis (Clontech, Palo Alto,Calif.) as being more abundant in the normal-subtracted glaucoma cDNAlibrary (FIG. 1B). TM cell lines used for pooling for Virtual Northernblot analysis were identical to those used in the cDNA subtractionanalysis.

EXAMPLE 2 Quantitative PCR

Additional verification of differential expression of CTSK was performedby Quantitative Real-Time PCR (QPCR). First strand cDNA was generatedfrom 1 μg of total RNA isolated from pooled normal or glaucoma TM celllines (identical to those used in the cDNA Subtraction analysis) usingrandom hexamers and Taqman Reverse Transcription reagents according tothe manufacturer's instructions (Applied Biosystems, Foster City,Calif.).

Measurement of CTSK gene expression by QPCR was performed using an ABIPrism 7700 Sequence Detection System (Applied Biosystems, Foster City,Calif.) essentially as described (Shepard et al. 2001). Primers for CTSKQPCR amplification were based on the sequence information in GenBankaccession # NM_(—)000396 and were designed using Primer Express software(Applied Biosystems, Foster City, Calif.). Forward and reverse primersequences were CATATGTGGGACAGGAAGAGAGTTG (nucleotides 734-758) andGGATCTCTCTGTACCCTCTGCATT (nucleotides 788-811), and the TaqMan (AppliedBiosystems, Foster City, Calif.) probe sequence wasAGCTGCCTTGCCTGTTGGGTTGTACA (nucleotides 761-786) with 6FAM and TAMRAattached to the 5′ and 3′ ends of the probe sequence, respectively.Amplification of the 78-bp CTSK amplicon was normalized to 18S ribosomalRNA levels in each sample using pre-developed 18S rRNA primer/probe set(20×18S Master Mix; Applied Biosystems, Foster City, Calif.). CTSK QPCRconsisted of 1× TaqMan Universal Mix (Applied Biosystems, Foster City,Calif.), 0.25×18S rRNA primer/probe set, 900 nM each CTSK primers, 100nM CTSK TaqMan probe, and 2.5 ng cDNA in a final volume of 25 μl.Thermal cycling conditions consisted of 50° C., 2 min, 95° C. 10 minfollowed by 40 cycles at 95° C., 15 sec, 60° C., 1 min. Quantitation ofrelative cDNA concentrations was done using the relative standard curvemethod as described in PE Biosystems User Bulletin #2 (AppliedBiosystems, Foster City, Calif.). Pooled glaucomatous TM cell line cDNA(identical to that used for the cDNA subtraction analysis) was also usedfor generating the relative standard curve. Data analysis was performedwith SDS software version 1.91 (Applied Biosystems, Foster City, Calif.)and MS Excel 97 (Microsoft, Redmond, Wash.). QPCR data are presented asmean±SEM of the CTSK/18S normalized ratio.

EXAMPLE 3 Affymetrix GeneChip Analysis

In addition to the identification of CTSK by cDNA subtraction analysis,CTSK was subsequently identified as upregulated in GTM cells byAffymetrix GeneChip (Affymetrix, Santa Clara, Calif.) analysis usingpooled normal (NTM94, NTM68B, NTM79B, and NTM55C) or glaucomatous TMcells (GTM19A, GTM54A, GTM62E&G, and SGTM152) (NTM=normal trabecularmeshwork; GTM=glaucomatous trabecular meshwork). Essentially, total RNAwas collected from the cell lines using TRIZOL reagent according to themanufacturers instructions (Invitrogen, Carlsbad, Calif.), pooled, andsubjected to reverse transcription, in vitro transcription, andbiotin-labeling of amplified cRNA according to standard Affymetrixprotocols (Affymetrix, Santa Clara, Calif.). The Affymetrix Human GenomeU133A/B GeneChip (Affymetrix, Santa Clara, Calif.) set was probed withlabeled cRNA from either the normal or glaucoma TM cells. HybridizedGeneChips were scanned with a GeneArray scanner (Agilent Technologies,Palo Alto, Calif.). Data was collected and analayzed using MicroarraySuite software (Affymetrix, Santa Clara, Calif.).

Subsequent data analysis was done with GeneSpring software (SiliconGenetics, Redwood City, Calif.). For each experiment, data werenormalized per chip by dividing each measurement by the 50^(th)percentile of all signal intensity measurements for that chip. Theexpression ratio for each gene was calculated by dividing the normalizedsignal per gene in the treated or diseased sample by the median for thatgene in the control sample for each experiment. Genes were selected foran expression level above the statistical background by using theCross-Gene Error Model and setting the baseline equal to the uniquebase/proportional value for each experiment. Only genes that wereflagged as present/marginal on the Affymetrix U133A GeneChip in allexperimental conditions were considered for analysis. RNA sources forthis study were derived from normal TM cell lines NTM94, NTM68B, NTM79B,and NTM55C and glaucoma TM cell lines GTM19A, GTM54A, GTM62E&G, andSGTM152. CTSK (GenBank #NM_(—)000396) is represented on the U133AGeneChip as probe set 202450_s_at. CTSK was detected at levels 4.3-foldhigher in glaucomatous than normal TM cells (FIG. 3).

EXAMPLE 4

Amount in weight % Cathepsin K inhibitor 0.01-5; 0.05-2; 0.1-1.0Hydroxypropylmethylcellulose 0.5 Sodium Chloride 0.8 BenzalkoniumChloride 0.01 EDTA 0.01 NaOH/HCl q.s. pH 7.4 Purified water q.s. 100 mL

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents which are both chemically and structurallyrelated may be substituted for the agents described herein to achievesimilar results. All such substitutions and modifications apparent tothose skilled in the art are deemed to be within the spirit, scope andconcept of the invention as defined by the appended claims.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

United States Patents

-   -   U.S. Pat. No. 5,830,850    -   U.S. Pat. No. 5,998,470    -   U.S. Pat. No. 6,034,077    -   U.S. Pat. No. 6,057,362

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F.,    “Dexamethasone induced ultrastructural changes in cultured human    trabecular meshwork cells,” CURR EYE RES 12:783 (1993).-   Yamashita, D. S. and Dodds, R. A., “Cathepsin K and the design of    inhibitors of cathepsin K,” CURR. PHARM. DES. 6:1-24 (2000).-   Yamashita, D. S., Dong, X., Oh, H. J., Brook, C. S., Tomaszek, T.    A., Szewczuk, L., Tew, D. G., Veber, D. F., “Solid-phase synthesis    of a combinatorial array of 1,3-bis(acylamino)-2-butanones,    inhibitors of the cysteine proteases cathepsins K and L,” J. COMB.    CHEM. 1:207-215 (1999).-   Zhao, B., Janson, C. A., Amegadzie, B. Y., D'Alessio, K., Griffin,    C., Hanning, C. R., Jones, C., Kurdyla, J., McQueney, M., Qiu, X.,    “Crystal structure of human osteoclast cathepsin K complex with    E-64,” NAT. STRUCT. BIOL. 4:109-111 (1997).

1. A method for treating glaucoma, said method comprising administeringto a patient in need thereof a therapeutically effective amount of acomposition comprising at least one cathepsin K antagonist.
 2. Themethod of claim 1, wherein the cathepsin K antagonist is selected fromthe group consisting of monensin, brefeldin A, tunicamycin and1,3-bis(acylamino)-2-propanone derivatives, cycloaltilisin 6,cycloaltilisin 7, AC-3-1, AC-3-3, AC-5-1, haploscleridamine,5-(2-morpholin-4-yl-thoxy)-benzofuran-2-carboxylic acid((S)-3-methyl-1-[3-oxo-1-[2-(3-pyridin-2-yl-phenyl)-ethenoyl]-azepan-4-ylcarbanoyl)-butyl)-amide(SB-331750), SB-357114, peptidomimetic aminomethyl ketones,α,α′-diacylamino ketones, alkoxymethyl ketones, cyanamides, pyridoxalpropionate derivatives (including Clik-164 and Clik-166), SB-290190,α-alkoxyketone derivatives, cyanamide derivatives, andN_(α)-acyl-α-amino acid-(arylaminoethyl)amides.
 3. The method of claim1, wherein the cathepsin K antagonist is an arylaminoethyl amide.
 4. Themethod of claim 1, wherein the cathepsin K antagost is selected from thegroup consisting of:(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboxamidothiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-cyanothiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-[2-(N-benzylcarboxamido)thiazol-4-yl]-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1-[2-[N′-3-methylpropyl)carboxamido]thiazol-4-yl)]-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-[2-[N′-2-phenylethyl)carboxamido]thiazol-4-yl)]-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboxythiazol-2-yl)-3′-methylbutyl]4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxythiadiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carbo-2,2,2-trifluoroethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxyoxadiazol-2-yl)-3′-methylbutyl]4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboxamidooxadiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-3-phenylpropanamide;(2S,1′S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(5-mercapto-1,2,4-oxadiazol-3-yl)-3′-methylbutyl]methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-mercaptothiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S)-2-(benzyloxycarbonyl)amino-N-(4-carboethoxythiazol-2-yl)methyl-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-benzyloxycarbonylthiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-4-methyl-N-[3′-methyl-1′-(2-phenoxycarbonylthiazol-4-yl)butyl]pentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-4-methyl-N-[3′-methyl-1′-[2-(2-methylpropyloxycarbonyl)thiazol-4-yl]butyl]pentanamide;(2R,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(carboethoxythiazol-2-yl)ethyl]-4-methylpentanamide;(2R,1′R)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carbethoxythiazol-2-yl)ethyl]-4-methylpentanamide;(2S,1′S)-N-[1′-(2-aminothiazol-4-yl)-3′-methylbutyl]-2-(benzyloxycarbonyl)amino-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(1S)-N-[4-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N′-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;N-benzyloxycarbonyl-L-leucinyl-N′-benzyloxycarbonyl-L-leucinyl-L-leucinylhydrazide;(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;2,2′-(N,N′-bis-benzyloxycarbonyl-L-leucinyl)carbohydrazide;2,2′-(N,N′-bis-cyclohexylacetyl)carbohydrazide;2,2′-(N,N′-bis-4-methylpentanoyl)carbohydrazide;2,2′-(N,N′-bis-cyclopentylacetyl)carbohydrazide;2,2′-(N,N′-bis-benzyloxycarbonylglycinyl)carbohydrazide;2,2′-(N,N′-bis-acetyl-L-leucinyl)carbohydrazide;2,2′-(N,N′-bis-benzyloxycarbonyl-L-alanyl)carbohydrazide;2-(N-benzyloxycarbonyl-L-leucinyl)-2′-[N′-(4-methylpentanoyl)]carbohydrazide;2,2′-(N,N′-bis-benzyloxycarbonyl-L-leucinyl)carbohydrazide;bis-(Cbz-leucinyl)-1,3-diamino-propan-2-one;bis-1,3-(4-phenoxy-benzoyl)-diamino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl-t-butylester)-amino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl)-amino-propan-2-one;bis-1,3-(Cbz-leucinyl)-diamino-(S)-butanone-2-one;1-(Cbz-leucinyl)-amino-3-(Cbz-phenylalanyl)-amino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(Cbz-norleucinyl)-amino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(Cbz-norvalinyl)-amino-propan-2-one;bis-1,3-(Cbz-leucinyl)-diamino-5-methyl-(S)-hexan-2-one;1-(acetyl-leucinyl)-amino-3-(4-phenoxy-benzoyl)-amino-propan-2-one;1-(Cbz-homo-leucinyl)-amino-(Cbz-leucinyl)-3-amino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one;bis-1,3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-one;bis-1,3-(4-phenoxy-phenyl sulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenylsulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(tosyl-amino)-propan-2-one;1-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one;1-(Cbz-homo-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one;1-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(2-benzofuransulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one;(S)-Phenylmethyl[1-[[[3-[benzyloxycarbonyl-leucinyl-amino]-2-oxopropyl]-1-(benzyl)amino]carbonyl]-3-methylbutyl]carbamate;(S)-Phenylmethyl[1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(benzyl)amino]carbonyl]-3-methylbutyl]carbamate;(S)-Phenylmethyl[1-[[[3-[(2-benzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate;1-[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4-pyridinylmethyl)]benzamide; (S)-Phenylmethyl[1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-1-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate;(S)-Phenylmethyl[1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-1-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N-(4-phenoxyphenylsulfonyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-alanyl)]-2′-[N-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenylbenzoyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-4-methoxybenzoyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenoxybenzoyl)]carbohydrazide;2-(N-acetyl)-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-acetyl-L-leucinyl)]-2′-[N′-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide;2-[N-(N-acetyl-L-alanyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-(N,N-dimethylaminomethyl)benzoyl)]]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-hydroxy-[3-(4-morpholinomethyl)]]benzoyl]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-[(N,N-dimethylaminomethyl)benzyloxy]carbonyl-L-leucinyl]carbohydrazide;2-(N-benzoyl)-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[3-(4-morpholinomethyl)benzoyl]]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-[3-N—N-dimethylamino)-1-propyloxy]benzoyl]]carbohydrazide;2-[N-(2-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[3-(4-pyridylmethoxy)benzoyl]]carbohydrazide;2-[N-(4-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(3-benzyloxy-5-methoxy)benzoyl]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(3-benzyloxy-5-dimethoxy)benzoyl]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(3-benzyloxy-5-ethoxy)benzoyl]carbohydrazide;2-[N-(N-benzyloxycarbonylglycinyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-prolinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenylphenylacetyl)]carbohydrazide;(2′S)-2-[N-(3-benzyloxybenzoyl)]-2′-[N′-N-benzyloxycarbonyl-2-aminobutyryl)]carbohydrazide;2,2′-[N,N′-[bis-4-phenylphenylacetyl)]]carbohydrazide;(2′RS)-2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[2-(4-phenylphenoxy)propionyl]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(4-methylpentanoyl)]carbohydrazide;(2RS,2′RS)-2,2′-[N,N′-[bis-[2-(4-phenylphenyl)-4-methylpentanoyl)]]]carbohydrazide;(2′RS)-2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;(2′RS)-2-[N-(3-benzyloxybenzoyl)]-2′-[N-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;2-[N-[3-(4-pyridylmethoxy)benzoyl]]-2′-[N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;(2RS)-2-[N-[2-(4-phenylphenyl)-4-methylpentanoyl)]]-2′-[N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[N-(4-phenylphenyl)-N-(2-methylpropyl)carbamoyl]]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-methyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(N-methyl-L-leucinyl)]carbohydrazide;(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-(4-phenoxyphenylsulfonyl)hydrazide;(1S)-N-[4-[1-(N-benzyloxycarbonyl-L-leucinylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N′-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-(4-phenylphenylacetyl)hydrazide;(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-[3-(4-pryidinylmethoxy)benzoyl]hydrazide;N-[2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N′-[2-[4-(1,2,3-thiadiazol-4-yl)phenyl]thiazol-4-ylcarbonyl]hydrazide;N-[2-[3-(4-chlorophenylsulfonylmethyl)thien-2-yl]thiazol-4-ylcarbonyl]-N′-[N-4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;(1S,2′RS)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-[2′-(4-phenylphenylacetyl)-4-methylpentanoyl-]hydrazide;N-[2-(3-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;(1RS)-N-[2-[1-(4-phenylphenyl)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-[N-methyl-N-(4-phenylphenyl)amino]thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-(N-benzyloxycarbonyl-L-leucinyl)-N′-[2-(4-phenylbenzyl)thiazol-4-ylcarbonyl]hydrazide;N-[2-(4-phenylphenylbenzyl)thiazol-4-ylcarbonyl]-N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-(N-benzyloxycarbonyl-L-leucinyl)-N′-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]hydrazide;N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)-N′-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]hydrazide;N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N′-[N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-(2-methoxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-(N,N-dimethylaminomethyl)benzyloxy]carbonyl-L-leucinyl]carbonhydrazide;(3S,4S)-3-(2S-2-benzyloxycarbonylamino-2-cyclohexyl-methyl-acetamido)-4-acetoxy-azetidin-2-one;(3S,4S)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-acetoxy-azetidin-2-one;(3S,4S)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-{4-(2S-2-amino-2-carboxy-ethyl)-phenoxy}-azetidin-2-one;(3S,4R)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}4-{4-(2S-2-amino-2-carboxy-ethyl)-phenoxy}-azetidin-2-one;(3S,4SR)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-phenylthio-azetidin-2-one;(3S,4SR)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-phenylsulfonyl-azetidin-2-one;(3S,4S)-3-{2S-2-(benzylaminocarbonyl)amino-2-cyclo-hexylmethyl-acetamido}-4-acetoxy-azetidin-2-one;(3S,4S)-3-{2S-2-(phenylethenylsulfonyl)amino-2-cyclohexylmethyl-acetamido}-4-acetoxy-azetidin-2-one;(3S,4S)-3-(2S-2-benzyloxycarbonylamino-2-cyclohexylmethyl-acetamido)-4-(3-methyl-phenoxy)-azetidin-2-one;(3S,4R)-3-(2S-2-benzyloxycarbonylamino-2-cyclohexylmethyl-acetamido)-4-(3-methyl-phenoxy)-azetidin-2-one;(3S,4S)-3-{2S-2-[3-(pyridin-4-yl)propenoyl]amino-2-cyclohexylmethyl-acetamido}4-phenoxy-azetidin-2-one;and(3S,4S)-3-{2S-2-[3-(pyridin-3-yl)propenoyl]amino-2-cyclohexylmethyl-acetamido}4-phenoxy-azetidin-2-one.5. A composition for the treatment of glaucoma, said compositioncomprising a therapeutically effective amount of at least one cathepsinK antagonist and a pharmaceutically acceptable excipient.
 6. Thecomposition of claim 5, wherein the cathepsin K antagonist is selectedfrom the group consisting of arylaminoethyl amides, monensin, brefeldinA, tunicamycin and 1,3-bis(acylamino)-2-propanone derivatives,cycloaltilisin 6, cycloaltilisin 7, AC-3-1, AC-3-3, AC-5-1,haploscleridamine, 5-(2-morpholin-4-yl-thoxy)-benzofuran-2-carboxylicacid((S)-3-methyl-1-[3-oxo-1-[2-(3-pyridin-2-yl-phenyl)-ethenoyl]-azepan-4-ylcarbanoyl)-butyl)-amide(SB-331750), SB-357114, peptidomimetic aminomethyl ketones,α,α′-diacylamino ketones, alkoxymethyl ketones, cyanamides, pyridoxalpropionate derivatives (including Clik-164 and Clik-166), SB-290190,α-alkoxyketone derivatives, cyanamide derivatives, andN_(α)-acyl-α-amino acid-(arylaminoethyl)amides.
 7. The composition ofclaim 5, wherein the cathepsin K antagonist is an arylaminoethyl amide.8. The composition of claim 5, wherein the cathepsin K antagonist isselected from the group consisting of:(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboxamidothiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[′-(2-cyanothiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-[2-(N′-benzylcarboxamido)thiazol-4-yl]-3′-methylbutyl]4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-[2-[N′-3-methylpropyl)carboxamido]thiazol-4-yl)]-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-[2-[N′-2-phenylethyl)carboxanmido]thiazol-4-yl)]-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]4-methylpentanamide;(2S,l′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxythiadiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carbo-2,2,2-trifluoroethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxyoxadiazol-2-yl)-3′-methylbutyl]4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboxamidooxadiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-3-phenylpropanamide;(2S,1′S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(5-mercapto-1,2,4-oxadiazol-3-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-mercaptothiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S)-2-(benzyloxycarbonyl)amino-N-(4-carboethoxythiazol-2-yl)methyl-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-benzyloxycarbonylthiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-4-methyl-N-[3′-methyl-1′-(2-phenoxycarbonylthiazol-4-yl)butyl]pentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-4-methyl-N-[3′-methyl-1′-[2-(2-methylpropyloxycarbonyl)thiazol-4-yl]butyl]pentanamide;(2R,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(carboethoxythiazol-2-yl)ethyl]-4-methylpentanamide;(2R,1′R)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carbethoxythiazol-2-yl)ethyl]-4-methylpentanamide;(2S,1′S)-N-[1′-(2-aminothiazol-4-yl)-3′-methylbutyl]-2-(benzyloxycarbonyl)amino-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(2-carboethoxythiazol-4-yl)-3′-methylbutyl]-4-methylpentanamide;(2S,1′S)-2-(benzyloxycarbonyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]4-methylpentanamide;2S,1′S)-2-(benzyloxycarbonyl-L-leucinyl)amino-N-[1′-(4-carboethoxythiazol-2-yl)-3′-methylbutyl]-4-methylpentanamide;(1S)-N-[4-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N′-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;N-benzyloxycarbonyl-L-leucinyl-N′-benzyloxycarbonyl-L-leucinyl-L-leucinylhydrazide;(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;2,2′-(N,N′-bis-benzyloxycarbonyl-L-leucinyl)carbohydrazide;2,2′-(N,N′-bis-cyclohexylacetyl)carbohydrazide;2,2′-(N,N′-bis-4-methylpentanoyl)carbohydrazide;2,2′-(N,N-bis-cyclopentylacetyl)carbohydrazide;2,2′-(N,N′-bis-benzyloxycarbonylglycinyl)carbohydrazide;2,2′-(N,N′-bis-acetyl-L-leucinyl)carbohydrazide;2,2′-(N,N′-bis-benzyloxycarbonyl-L-alanyl)carbohydrazide;2-(N-benzyloxycarbonyl-L-leucinyl)-2′-[N′-(4-methylpentanoyl)]carbohydrazide;2,2′-(N,N′-bis-benzyloxycarbonyl-L-leucinyl)carbohydrazide;bis-(Cbz-leucinyl)-1,3-diamino-propan-2-one;bis-1,3-(4-phenoxy-benzoyl)-diamino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl-t-butylester)-amino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(Cbz-glutamyl)-amino-propan-2-one;bis-1,3-(Cbz-leucinyl)-diamino-(S)-butanone-2-one;1-(Cbz-leucinyl)-amino-3-(Cbz-phenylalanyl)-amino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(Cbz-norleucinyl)-amino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(Cbz-norvalinyl)-amino-propan-2-one;bis-1,3-(Cbz-leucinyl)-diamino-5-methyl-(S)-hexan-2-one;1-(acetyl-leucinyl)-amino-3-(4-phenoxy-benzoyl)-amino-propan-2-one;1-(Cbz-homo-leucinyl)-amino-(Cbz-leucinyl)-3-amino-propan-2-one;1-(Cbz-leucinyl)-amino-3-(acetyl-leucinyl)-amino-propan-2-one;bis-1,3-(4-(3-chloro-2-cyano-phenoxy)-phenyl sulfonamido)-propan-2-one;bis-1,3-(4-phenoxy-phenyl sulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(4-(3-chloro-2-cyano-phenoxy)-phenylsulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(tosyl-amino)-propan-2-one;1-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one;1-(Cbz-homo-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one;1-(Cbz-leucinyl)-amino-3-((4-phenoxy-phenyl)-sulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-propan-2-one;1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-one;(S)-Phenylmethyl[1-[[[3-[benzyloxycarbonyl-leucinyl-amino]-2-oxopropyl]-1-(benzyl)amino]carbonyl]-3-methylbutyl]carbamate;(S)-Phenylmethyl[1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(benzyl)amino]carbonyl]-3-methylbutyl]carbamate;(S)-Phenylmethyl[1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate;1-[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-3-(4-pyridinylmethyl)]benzamide; (S)-Phenylmethyl[1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-1-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate;(S)-Phenylmethyl[1-[[[3-[(2-dibenzofuranylsulfonyl)amino]-2-oxopropyl]-1-(4-pyridinylmethyl)amino]carbonyl]-3-methylbutyl]carbamate;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenoxyphenylsulfonyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-alanyl)]-2′-[N-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenylbenzoyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-4-methoxybenzoyl)]carbohydrazide;2-[N-N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenoxybenzoyl)]carbohydrazide;2-(N-acetyl)-2‘-N’-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-acetyl-L-leucinyl)]-2′-[N′-(N-benzyloxycarbonyl-L-alanyl)]carbohydrazide;2-[N-(N-acetyl-L-alanyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-(N,N-dimethylaminomethyl)benzoyl)]]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-hydroxy-[3-(4-morpholinomethyl)]]benzoyl]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-[(N,N-dimethylaminomethyl)benzyloxy]carbonyl-L-leucinyl]carbohydrazide;2-(N-benzoyl)-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[3-(4-morpholinomethyl)benzoyl]]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl)-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-[3-N—N-dimethylamino)-1-propyloxy]benzoyl]]carbohydrazide;2-[N-(2-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[3-(4-pyridylmethoxy)benzoyl]]carbohydrazide;2-[N-(4-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(3-benzyloxy-5-methoxy)benzoyl]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(3-benzyloxy-4,5-dimethoxy)benzoyl]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(3-benzyloxy-5-ethoxy)benzoyl]carbohydrazide;2-[N-(N-benzyloxycarbonylglycinyl)]-2′-[N′-(N-benzyloxycarbonyl-L-leucinyl)]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-L-prolinyl)]carbohydrazide;2-[N-N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(4-phenylphenylacetyl)]carbohydrazide;(2′S)-2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-2-aminobutyryl)]carbohydrazide;2,2′-[N,N-[bis-4-phenylphenylacetyl)]]carbohydrazide;(2′RS)-2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[2-(4-phenylphenoxy)propionyl]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(4-methylpentanoyl)]carbohydrazide;(2RS,2′RS)-2,2′-[N,N′-[bis-[2-(4-phenylphenyl)-4-methylpentanoyl)]]]carbohydrazide;(2′RS)-2-[N-N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;(2′RS)-2-[N-(3-benzyloxybenzoyl)]-2′-[N-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;2-[N-[3-(4-pyridylmethoxy)benzoyl]]-2′-[N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;(2RS)-2-[N-[2-(4-phenylphenyl)-4-methylpentanoyl)]]-2′-[N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[′-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[′-[2-(4-phenylphenyl)-4-methylpentanoyl)]]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[N-(4-phenylphenyl)-N-(2-methylpropyl)carbamoyl]]carbohydrazide;2-[N-(3-benzyloxybenzoyl)]-2′-[N′-(N-methyl-L-leucinyl)]carbohydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-(N-methyl-L-leucinyl)]carbohydrazide;(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-(4-phenoxyphenylsulfonyl)hydrazide;(1S)-N-[4-[1-(N-benzyloxycarbonyl-L-leucinylamino)-3-methylbutyl]thiazol-2-ylcarbonyl]-N′-(N-benzyloxycarbonyl-L-leucinyl)hydrazide;(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-(4-phenylphenylacetyl)hydrazide;(1S)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-[3-(4-pryidinylmethoxy)benzoyl]hydrazide;N-[2-(2-chlorophenoxymethyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]-N′-[2-[4-(1,2,3-thiadiazol-4-yl)phenyl]thiazol-4-ylcarbonyl]hydrazide;N-[2-[3-(4-chlorophenylsulfonylmethyl)thien-2-yl]thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;(1S,2′RS)-N-[2-[(1-benzyloxycarbonylamino)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-[2′-(4-phenylphenylacetyl)-4-methylpentanoyl-]hydrazide;N-[2-(3-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;(1RS)-N-[2-[1-(4-phenylphenyl)-3-methylbutyl]thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-[N-methyl-N-(4-phenylphenyl)amino]thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-(N-benzyloxycarbonyl-L-leucinyl)-N′-[2-(4-phenylbenzyl)thiazol-4-ylcarbonyl]hydrazide;N-[2-(4-phenylphenylbenzyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-(N-benzyloxycarbonyl-L-leucinyl)-N′-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]hydrazide;N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-(N-benzyloxycarbonyl-N-methyl-L-leucinyl)-N′-[2-(2-benzyloxyphenyl)thiazol-4-ylcarbonyl]hydrazide;N-[2-[N-(2-methylpropyl)-N-phenYlamino]thiazol-4-ylcarbonyl]-N′-[N-(2-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-[N-(2-methylpropyl)-N-phenylamino]thiazol-4-ylcarbonyl]-N′-[N-(3-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;N-[2-(2-methoxyphenyl)thiazol-4-ylcarbonyl]-N′-[N-(4-pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2′-[N′-[4-(N,N-dimethylaminomethyl)benzyloxy]carbonyl-L-leucinyl]carbonhydrazide;(3S,4S)-3-(2S-2-benzyloxycarbonylamino-2-cyclohexyl-methyl-acetamido)-4-acetoxy-azetidin-2-one;(3S,4S)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-acetoxy-azetidin-2-one;(3S,4S)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-{4-(2S-2-amino-2-carboxy-ethyl)-phenoxy}-azetidin-2-one;(3S,4R)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-{4-(2S-2-amino-2-carboxy-ethyl)-phenoxy}-azetidin-2-one;(3S,4SR)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-phenylthio-azetidin-2-one;(3S,4SR)-3-{2S-2-(3-phenylpropionoyl)amino-2-cyclo-hexylmethyl-acetamido}-4-phenylsulfonyl-azetidin-2-one;(3S,4S)-3-{2S-2-(benzylaminocarbonyl)amino-2-cyclo-hexylmethyl-acetamido}-4-acetoxy-azetidin-2-one;(3S,4S)-3-{2S-2-(phenylethenylsulfonyl)amino-2-cyclohexylmethyl-acetamido}-4-acetoxy-azetidin-2-one;(3S,4S)-3-(2S-2-benzyloxycarbonylamino-2-cyclohexylmethyl-acetamido)-4-(3-methyl-phenoxy)-azetidin-2-one;(3S,4R)-3-(2S-2-benzyloxycarbonylamino-2-cyclohexylmethyl-acetamido)-4-(3-methyl-phenoxy)-azetidin-2-one;(3S,4S)-3-{2S-2-[3-pyridin-4-yl)propenoyl]amino-2-cyclohexylmethyl-acetamido}-4-phenoxy-azetidin-2-one;and (3S,4S)-3-{2S-2-[3-(pyridin-3-yl)propenoyl]amino-2-cyclohexylmethyl-acetamido}4-phenoxy-azetidin-2-one.